Targeted Polymeric Nanoparticles for Brain Delivery of High Molecular Weight Molecules in Lysosomal Storage Disorders

Abstract

Lysosomal Storage Disorders (LSDs) are a group of metabolic syndromes, each one due to the deficit of one lysosomal enzyme. Many LSDs affect most of the organ systems and overall about 75% of the patients present neurological impairment. Enzyme Replacement Therapy, although determining some systemic clinical improvements, is ineffective on the CNS disease, due to enzymes' inability to cross the blood-brain barrier (BBB). With the aim to deliver the therapeutic enzymes across the BBB, we here assayed biodegradable and biocompatible PLGA-nanoparticles (NPs) in two murine models for LSDs, Mucopolysaccharidosis type I and II (MPS I and MPS II). PLGA-NPs were modified with a 7-aminoacid glycopeptide (g7), yet demonstrated to be able to deliver low molecular weight (MW) molecules across the BBB in rodents. We specifically investigated, for the first time, the g7-NPs ability to transfer a model drug (FITC-albumin) with a high MW, comparable to the enzymes to be delivered for LSDs brain therapy. In vivo experiments, conducted on wild-type mice and knockout mouse models for MPS I and II, also included a whole series of control injections to obtain a broad preliminary view of the procedure efficiency. Results clearly showed efficient BBB crossing of albumin in all injected mice, underlying the ability of NPs to deliver high MW molecules to the brain. These results encourage successful experiments with enzyme-loaded g7-NPs to deliver sufficient amounts of the drug to the brain district on LSDs, where exerting a corrective effect on the pathological phenotype.

Nanotechnology applied to treatment of mucopolysaccharidoses

“…Recently, a study demonstrated that biodegradable and biocompatible PLGA-nanoparticles modified with a 7-aminoacid glycopeptide (g7) were able to deliver a model drug (FITC-albumin) in MPS type I and II mice across the BBB. This result encourages experiments with enzyme-loaded g7-nanoparticles to the brain [73].…”

Lysosomal enzyme replacement therapies: Historical development, clinical outcomes, and future perspectives

“…This is ideal not only for proper activity of lysosomal enzymes but also to help restore lysosomal acidification, which is otherwise defective in LDs [117, 405]. PLGA nanoparticles targeted to intercellular adhesion molecule 1 (ICAM-1), discussed in Section 5.4, or by a small glycopeptide (g7), have been shown to significantly enhance transport of enzymes into the brain [406, 407]. In the latter case, albumin was used as a model protein and these nanoparticles were examined in animal models of MPS I and II [407].…”

“…PLGA nanoparticles targeted to intercellular adhesion molecule 1 (ICAM-1), discussed in Section 5.4, or by a small glycopeptide (g7), have been shown to significantly enhance transport of enzymes into the brain [406, 407]. In the latter case, albumin was used as a model protein and these nanoparticles were examined in animal models of MPS I and II [407]. As shown in Figure 3C, only g7-targeted PLGA nanoparticles, but not nanoparticles lacking g7 glycopeptide, were found in the brain of animals 2 h after intravenous administration [407].…”

“…In the latter case, albumin was used as a model protein and these nanoparticles were examined in animal models of MPS I and II [407]. As shown in Figure 3C, only g7-targeted PLGA nanoparticles, but not nanoparticles lacking g7 glycopeptide, were found in the brain of animals 2 h after intravenous administration [407]. As a protein which helps maintain the oncotic pressure in tissues, albumin is known by its ability to cross certain endothelial barriers, which may have contributed to this outcome, but this remains an encouraging result.…”

Green Intelligent Nanomaterials by Design (Using Nanoparticulate/2D-Materials Building Blocks) Current Developments and Future Trends

“…The inorganic NPs embedded polymer matrix showed enhanced performance as discussed in a recent review dealing with preparation and characterization of cytocompatible multifunctional polymeric NPs by analyzing their fluorescence efficiency, the nature of the artificial cell-membrane structure, and their performance as in-cell devices [68]. In enzyme replacement therapy of lysosomal storage disorders (LSDs), using PLGA NPs modified with 7-aminoacid glycopeptide (g7) NPs along with high MW drug (FITC-albumin) improved the barrier crossing of albumin while delivering the drug to the brain [69].…”